Expression of erythropoietin receptor in select non-hematopoietic tissue provides for erythropoietin response beyond erythroid progenitor cell survival, proliferation and differentiation. Bone marrow is the primary site of erythropoietin activity and erythropoietin effects on bone remodeling have been reported to be associated with both improved bone healing as well as with bone resorption. We observed that in addition to the increase in hematocrit, erythropoietin treatment in mice decreased trabecular bone mineral density and trabecular number, and increased trabecular spacing. Mice with chronic elevated erythropoietin also exhibited decreased trabecular bone and cortical bone. Increased TRAP stained osteoclasts were observed in femur sections from these mice and enhanced osteoclastogenesis in corresponding whole bone marrow cultures. These data provide evidence that in the bone marrow, increased erythropoietin stimulated hematopoietic activity is accompanied by erythropoietin stimulated bone remodeling with decreased trabecular bone mineral density. The marrow space expands as a consequence of the increased bone resorption.